Comparison of the prognostic impact of IPI and PIT in peripheral T-cell lymphoma in real-world practice with a large elderly population

We compared the predictive ability of the International Prognostic Index (IPI), a frequently used prognostic model for peripheral T-cell lymphoma (PTCL), with that of a type-specific prognostic model, the Prognostic Index for PTCL-U (PIT). We retrospectively analyzed 113 patients diagnosed with PTCL. The median age was 67 years (range, 16–88 years), 75 patients (66%) were male, and the most common disease type was PTCL, not otherwise specified (69%). With a median follow-up of 6.8 years (interquartile range, 2.7–9.9 years), 5-year survival rates for the four groups in IPI were 85%, 62%, 49%, and 13%, respectively. Similarly, 5-year survival rates for the four groups in PIT were 83%, 64%, 49%, and 19%, respectively. The area under the receiving operating characteristic curve for predicting mortality from PIT (0.725) was not significantly different from that from the IPI (0.685, P = 0.134). Multivariable analysis showed that performance status ≥ 2 (P < 0.0001) and extranodal lesions ≥ 2 (P = 0.029) were significantly associated with lower overall survival. The present study found no significant difference in prognostic ability between the IPI and PIT for PTCL, and both models appear useful as predictive models.

Peripheral T-cell lymphoma (PTCL) represents a heterogeneous group of aggressive lymphomas arising from mature T-cells 1 .The incidence of PTCL is higher in Asia than in Europe, and risk factors such as genetic factors, immune abnormalities, environmental factors, and infectious causes have been proposed 2 .Epstein-Barr virus (EBV)-associated PTCL is more common in Asia, where EBV infection is associated with inferior outcomes 3 .CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) or CHOP-like regimens such as THP-COP (pirarubicin, cyclophosphamide, vincristine, and prednisolone) are frequently used to treat patients with PTCL, but the prognosis has not been as good as that of patients with aggressive B-cell lymphoma 4 .In population-based studies, most PTCL patients progress or relapse following the first therapy, and long-term overall survival (OS) rates are within the range of 20-40% 5 .The more accurate the prognosis that can be determined during diagnosis or before treatment, the more appropriate the management that can be provided.
The International Prognostic Index (IPI) was developed in 1993 to identify patients with aggressive non-Hodgkin lymphoma (NHL) with poor prognosis 6 .Age, performance status (PS), lactate dehydrogenase (LDH), clinical stage, and extranodal involvement are used to calculate the IPI score.The IPI was primarily based on aggressive B-cell lymphoma rather than T-cell lymphoma but has shown an ability to stratify PTCL patients 7,8 .The Prognostic Index for PTCL-U (PIT) is a revised version of the IPI developed in 2004, mainly for PTCL, not otherwise specified (PTCL-NOS) 9 .The PIT includes three features of the IPI (age, PS, and LDH) along with bone marrow (BM) involvement.Although the PIT model was initially reported to offer better predictive ability than the IPI model, other studies found no difference between the two models [10][11][12][13][14] .
Since no studies have directly compared these two models using statistical methods, no conclusions have been reached regarding which model offers the better prognostic ability.Japan has the highest rate of aging in the world 15 , which brings with it many opportunities to treat elderly PTCL patients.However, relatively few studies have included high proportions of elderly PTCL patients.Therefore, we decided to directly compare the predictive powers of IPI and PIT in real-world Japanese patients with PTCL to determine which prognostic model is statistically superior.

Patient characteristics
Of the 132 patients who met the inclusion criteria during the study period, we excluded 5 patients with missing clinical information and 14 who did not receive chemotherapy (Supplementary Fig. S1).For the remaining 113 patients, their characteristics at diagnosis are presented in Table 1.The median age was 67 years (range, 16-88 years), and 75 patients (66.4%) were male.The most common disease type was PTCL-NOS (69.0%), and the second most common was angioimmunoblastic T-cell lymphoma (AITL) (

Comparison of prognostic impacts of IPI and PIT
When receiver operating characteristic (ROC) curves for OS were generated, and areas under the curve (AUCs) were compared, AUC for IPI score was 0.725 (95%CI 0.636-0.814)and AUC for PIT score was 0.685 (95%CI 0.593-0.778),with no significant difference between scores (P = 0.134) (Fig. 2a).For PFS, the AUC for IPI score was 0.742 (95% CI 0.646-0.837),and the AUC for PIT score was 0.711 (95% CI 0.614-0.808),with no significant difference between scores (P = 0.260) (Fig. 2b).In a subgroup analysis of patients treated with CHOP, the AUC for IPI score was significantly higher than that for PIT score for both OS (0.710 vs. 0.634, P = 0.035) and PFS (0.754 vs. 0.685, P = 0.035) (Fig. 2c,d).On the other hand, among patients treated with THP-COP, no significant difference in AUC was detected between IPI and PIT scores for both OS (0.747 vs. 0.742, P = 0.898) and PFS (0.755 vs. 0.765, P = 0.830) (Fig. 2e,f).www.nature.com/scientificreports/ In addition to the primary analyses, we conducted post-hoc evaluations using calibration plots and decision curve analyses to further compare the prognostic abilities of the IPI and PIT.Calibration plots for both OS and PFS showed no clinically relevant differences between the IPI and PIT (Fig. 3).Similarly, decision curve analyses for OS and PFS revealed nearly identical curves for both the IPI and PIT (Fig. 4).

Multivariable analysis of IPI and PIT factors
Multivariable analysis of IPI and PIT factors using Cox proportional hazards modeling showed that Eastern Cooperative Oncology Group (ECOG) PS ≥ 2 (hazard ratio [HR] 3.30, 95% CI 1.82-6.01;P < 0.0001) and extranodal lesions ≥ 2 (HR 2.05; 95% CI 1.08-3.90;P = 0.029) were significantly associated with OS and ECOG PS ≥ 2 (HR 1.84, 95% CI 1.1.0-3.07;P = 0.021) was significantly associated with PFS.Clinical stage III/IV and BM involvement were not significantly associated with OS or PFS (Table 2).We performed multivariable analysis with B symptoms and upfront auto-SCT as covariates in a post-hoc analysis.The results showed that clinical  www.nature.com/scientificreports/stage III/IV was significantly associated with PFS (HR 2.49, 95% CI 1.08-5.79,P = 0.033), but other results were generally the same.

Comparison of IPI and PIT with NCCN-IPI
We compared the National Comprehensive Cancer Network (NCCN)-IPI with IPI and PIT in a post-hoc analysis.NCCN-IPI was able to stratify PTCL patients into four groups for OS and PFS (Supplementary Fig. S3).

Discussion
In the present study, we have demonstrated no significant differences in the predictive abilities of IPI and PIT for PTCL.We also showed that IPI and PIT offer applicable predictive models for PTCL in real-world practice with a large elderly population.Given the lack of difference between the IPI and PIT, using the PIT with its four indices (age, PS, LDH, and BM involvement) is easier than IPI using five indices (age, PS, LDH, extranodal involvement, and clinical stage).In terms of prognostication, BM biopsy has shown the potential to simplify testing (e.g., PET-CT and endoscopy) for staging and the assessment of extranodal disease.However, we cannot conclude that BM involvement alone is sufficient for evaluation, because multivariable analysis did not identify BM involvement as an independent prognostic factor, whereas the presence of two or more extranodal lesions was a significant prognostic factor.In addition to age (> 60 years), ECOG PS (≥ 2), and LDH (above the upper limit of normal) identified by the IPI, PIT, which was proposed by the Intergruppo Italiano Linfomi, identified BM involvement as a poor prognostic factor 9 .In that study, the PIT model was described as offering superior predictive ability compared to the IPI based on the superior log-rank test statistic (66.79 vs. 55.94), but no direct statistical comparisons were made 9 .BM infiltration was considered a prognostic factor in the univariate analysis when the IPI was developed but was not selected when the prognostic model was created 6 .In addition, Weisenburger et al. retrospectively examined 340 PTCL-NOS patients and found that BM infiltration did not represent a robust predictor of OS (P = 0.03).Based on the results of the present analysis and previous reports 11 , PIT, which assesses BM infiltration, may not be clearly superior to IPI for predicting the survival of PTCL patients.Indeed, the presence of ≥ 2 extranodal lesions, but not BM infiltration, was significantly associated with OS in the present study.On the other hand, BM infiltration has been reported as a prognostic factor for patients with PTCL who undergo upfront auto-SCT 16 , indicating that its impact may vary depending on the treatment modality.In our study, only 12 patients (10.6%) underwent upfront auto-SCT, so BM infiltration may not have had a significant impact on prognosis.Prognostic factors for PTCL can differ depending on the treatment regimen.In a subgroup analysis focused on treatment regimens, the IPI demonstrated significantly greater accuracy in prognostic predictions than the PIT when treating PTCL with CHOP.Conversely, no significant difference between the IPI and PIT was observed for PTCL cases treated with THP-COP.As brentuximab vedotin combined with CHP (BV-CHP) is currently the standard of care for CD30-positive PTCL and anaplastic large-cell lymphoma (ALCL) 17 , the efficacy of the IPI and PIT within this treatment context warrants further investigation.
Various other prognostic factors for PTCL have been investigated.For instance, the International Peripheral T-Cell Lymphoma Project score (IPTCLP) was investigated for PTCL-NOS and AITL 18 .This prognostic index included age, PS, and platelet cell count (≤ 150 × 10 9 /L vs. > 150 × 10 9 /L) to divide patients into four groups.This study showed inferior OS in all but the low-risk group for the three indices of IPI, PIT, and IPTCLP.The modified PIT (m-PIT) is an updated version of the PIT for PTCL-NOS and AITL 19 .The m-PIT included age, PS, LDH, and Ki-67 (≤ 80% vs. > 80%) to divide patients into three groups.This score was associated with patient outcome (P < 0.0001) and was found to be more robust than PIT (P = 0.0043), but direct statistical comparisons to the PIT were not made.Gutiérrez-García et al. compared four prognostic indices (IPI, PIT, IPTCLP, m-PIT) in 122 PTCL patients (22 with ALCL, 56 with PTCL-NOS, 44 with others) 10 .Multivariable analysis including these four prognostic indices identified IPTCLP as the most important prognostic factor for predicting OS (relative risk [RR] 3.52, 95%CI 2.01-7.12,P = 0.0001).In a similar analysis limited to 56 PTCL-NOS patients, IPTCLP was also the most significant prognostic factor (RR 7.69, 95%CI 2.21-13.17,P = 0.002).Yamasaki et al. performed and AITL (n = 128) patients, revealing that better c-statistics (> 0.7) were only found for the IPI score for OS in PTCL-NOS 14 .However, in a study comparing three prognostic indices (IPI, PIT, and NCCN-IPI) in patients with ALCL without anaplastic large-cell lymphoma kinase (ALK) (n = 152), AITL (n = 145) and PTCL-NOS (n = 306), NCCN-IPI appeared to separate prognostic groups, although this difference did not result in markedly better c-statistics 13 .Therefore, even evaluating these reports overall, no conclusion has been reached regarding which prognostic index is best for patients with PTCL.This study was conducted as a multicenter cohort study, which allowed us to collect many patients with PTCL and conduct long-term follow-up.However, the study had several limitations.First, this was a retrospective study and may have included selection bias.Second, this study included numerous disease types, so we could not study any specific disease type.Third, comparisons or combinations with other prognostic indicators, such as IPTCLP and m-PIT, were not examined.Additional validation using a larger collection of cases is needed in the future.
In conclusion, IPI and PIT are useful as predictive models for PTCL, with no models showing significant differences in prognostic performance.

Figure 1 .
Figure 1.Kaplan-Meier curves of OS and PFS according to the IPI and PIT.(a,b) OS (a) and PFS (b) according to the IPI.(c,d) OS (c) and PFS (d) according to the PIT.OS overall survival, PFS progression-free survival, IPI International Prognostic Index, PIT Prognostic Index for PTCL-U.

Figure 2 .
Figure 2. Comparison of ROC curves between the IPI and PIT.Solid lines represent the AUC for the IPI, and dotted lines represent the AUC for the PIT.(a,b) OS (a) and PFS (b) in all patients.(c,d) OS (c) and PFS (d) in patients treated with CHOP.(e,f) OS (e) and PFS (f) in patients treated with THP-COP.OS overall survival, PFS progression-free survival, ROC receiver operating characteristic, AUC area under the curve, IPI International Prognostic Index, PIT Prognostic Index for PTCL-U.

Figure 3 .
Figure 3. Calibration plot for OS and PFS by IPI and PIT.(a) OS according to the IPI.(b) PFS according to the IPI.(c) OS according to the PIT.(d) PFS according to the PIT.OS overall survival, PFS progression-free survival, IPI International Prognostic Index, PIT Prognostic Index for PTCL-U.

Figure 4 .
Figure 4. Decision curve analysis comparing the prognostic abilities of IPI and PIT in predicting (a) OS and (b) PFS.gray line represents the net benefit of treating all patients, assuming all patients survive.The black line represents the net benefit if all patients were treated in the same way, assuming all patients die.The red dotted line represents the net benefit if patients were treated according to IPI.The black dotted line represents the net benefit if patients were treated according to PIT.OS overall survival, PFS progression-free survival, IPI International Prognostic Index, PIT Prognostic Index for PTCL-U.

Table 1 .
Patient characteristics at diagnosis.AITL angioimmunoblastic T-cell lymphoma, ALCL anaplastic large cell lymphoma, ALK anaplastic lymphoma kinase, BM bone marrow, EATL enteropathy-associated T-cell lymphoma, ECOG PS Eastern Cooperative Oncology Group performance status, HSTL hepatosplenic T-cell lymphoma, IPI International Prognostic Index, LDH lactate dehydrogenase, PIT Prognostic Index for PTCL-U, PTCL-NOS peripheral T-cell lymphoma, not otherwise specified, ULN upper limit of normal.